Heart failure due to systolic dysfunction is a disease of epidemic proportions in the U.S. with over 5 million effected individuals. Heart failure accounts for over one million hospitalizations, 400,000 deaths, and 40 billion dollars in health care expenses each year with a 5-year survival of less than 50% in severely affected individuals. Recent advances in pharmacological and device therapy have improved symptoms, decreased hospitalizations and lengthened survival to some extent. Heart failure is a progressive disease, however, and many patients eventually develop unremitting end-stage symptoms. Transplantation provides the only definitive treatment for these patients, but the small donor supply limits this therapy to only a few patients. More recently, the development of mechanical left ventricular assist devices (LVADs) has provided a novel "bridge" to transplantation. The increasing use of LVADs also provides the opportunity to test whether novel therapies such as gene transfer are safe and potentially efficacious. The sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) loads calcium into the sarcoplasmic reticulum (SR) and is downregulated in heart failure. Restoring SERCA2a levels using adenoviral or adeno-associated viral vectors has been shown to improve function, metabolism and/or survival in animal models using adenoviral and adeno-associated viral (AAV) gene transfer. During the first funding period, we have begun to test whether direct injection of an AAV expressing SERCA2a (AAV6-CMV-SERCA2a) at the time of LVAD placement in heart failure patients is safe and can restore SERCA2a expression to normal. We will extend our prior studies during the next funding period. We will: 1) compare direct injection vs. intracoronary perfusion and ubiquitous vs. cardiac specific promoters as the method of gene delivery in animal models of ischemic and non-ischemic cardiomyopathies; 2) perform a Phase 1 clinical trial testing the safety and potential efficacy of two different methods of global delivery of AAV6-SERCA2a at the time of LVAD placement; 3) perform a Phase 1/2 clinical trial to test the safety and potential efficacy of this treatment in heart failure patients having other cardiac surgical procedures; and 4) begin preclinical testing of other genes that may improve calcium cycling in the heart. These studies will determine the potential of gene transfer using SERCA2a as a treatment for patients with advanced heart failure.